Seasonal influenza imposes a significant socio-economic burden on humanity. Vaccination, the best hope for reducing the impact of influenza, is even under optimal circumstance effective in only 60% of individuals. The difficulty, of course, stems from the protean ability of influenza A virus (IAV) to rapidly escape existing immunity. IAV evolved an error prone polymerase that drives the rapid antigenic evolution of the two virion surface glycoproteins, neuraminidase (NA) and hemagglutinin (HA). Since the most potent antibodies (Abs) at neutralizing viral infectivity (neutralizing Abs, NAbs) are directed the head of the HA, amino acid substitutions in this region enable IAV to evade antibody (Ab)-based immunity. We are studying how IAV evolves under antibody pressure in vitro and in vivo, using ultra deep sequencing to detect mutations that reduce antibody affinity for IAV antigens and as well as epistatic alterations that mitigate fitness costs incurred by escape mutations. We are also studying the B cell response to IAV antigens, and have devised a novel approach that has enabled us for the first time to characterized the immunodominance hierarchy of antibody responses for distinct antigenic sites on the hemagglutinin glycoprotein.